4/21/2018 Capturing the Clinical Discosures Heterogeneity of Pulmonary Vascular • The University Medical Center Groningen contracts with Actelion, Lilly and Pfizer for consultancy Disease in Children activities of RMF Berger R.M.F. Berger • No relevant disclosures related to this presentation 11th International Conference Neonatal and Childhood Pulmonary Vascular Disease San Francisco 2018 University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 1
4/21/2018 Pulmonary Hypertension Congenital Heart Defects University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands PH CHD Panama classification of pediatric pulmonary hypertensive vascular disease Del Cerro et al. Pulm Circ 2011 University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 2
4/21/2018 Clinical classification of PH: WSPH (Nice) Heterogeneity vs Classification 1. Pulmonary arterial hypertension 3. PH due to lung diseases and/or hypoxia 1.1 Idiopathic PAH 3.1 COPD 1.2 Heritable PAH 3.2 Interstitial lung disease • Etiology 3.3 mixed restrictive and obstructive pattern 1.2.1 BMPR2 3.4 Sleep-disordered breathing 1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3 • Phenotype 1.2.3 Unknown 3.5 Alveolar hypoventilation disorders 1.3 Drug- and toxin-induced 3.6 Chronic exposure to high altitude • Co-morbidities 1.4 Associated with: 3.7 Developmental lung diseases 1.4.1 Connective tissue disease 3.7.1 Congenital diaphragmatic hernia • Clinical course 3.7.2 Bronchopulmonary dysplasia 1.4.2 HIV infection 4. CTEPH 1.4.3 Portal hypertension • Genotype 5. PH with unclear multifactorial mechanisms 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 5.1 Haematological disorders: chronic haemolytic anaemia, • Pathophysiologic mechanisms myeloproliferative disorders, splenectomy 1’ Pulmonary veno-occlusive disease &/or pulmonary capillary haemangiomatosis 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, • Biomarkers 1’’ Persistent PH of the newborn (PPHN) neurofibromatosis, vasculitis 2. PH due to LHD 5.3 Metabolic disorders: glycogen storage disease, • Treatment response 2.1 LV systolic dysfunction Gaucher disease, thyroid disorders 2.2 LV diastolic dysfunction 5.4 Others: segmental PH, tumoural obstruction, fibrosing 2.3 Valvular disease mediastinitis, chronic renal failure 2.4 Congenital/acquired left heart inflow/outflow obstruction University Medical Center Groningen University Medical Center Groningen Simonneau G, et al . J Am Coll Cardiol 2013; The Netherlands The Netherlands Classification… Characteristics of a Useful Classification System for who? Simple yet useful • Broad but not diffuse (e.g., “encyclopedic”) • Practitioners and care providers Patients and Families Internally consistent and easy to apply between providers and centers • Provides a common language • Subspecialists: Patient-Oriented Enhance care and research approaches to improve: • - NICU - Cardiology Investigators - Early identification or anticipation of PH in at-risk subjects - Pulmonary - PICU - CICU - Others - More rapidly obtain correct diagnosis Lab-Oriented - Guide effective evaluation and therapies Investigators Pharmaceuticals - Recognize critical features, common co-morbidities and Epidemiologists disease modifiers Insurance Companies Regulatory - Develop disease-specific strategies (FDA, EMA) Slide courtesy of Steven Abman Slide courtesy of Steven Abman University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 3
4/21/2018 Pediatric Pulmonary Hypertension Epidemiology Pediatric PAH Epidemiology of Associated Conditions data from large registries Pediatric Pulmonary Hypertension in the Netherlands, Period 1991-2005 TOPP 1 Reveal-children 2 Reveal-Adults 3 TOPP 1 Reveal-children 2 3265 Patients, n Patients, n 362 362 216 216 2525 pediatric PH patients Age at Dx (yrs), median Age at Dx (yrs), median 7.5 7.5 7 7 53 Female, % 59 64 80 Female, % 59 64 Group 1: PAH 317 (88) 216 (100) 2525 (100) Group 1: PAH 317 (88) 216 (100) IPAH/HPAH IPAH/HPAH 212 (53) 212 (53) 122 (56) 122 (56) 1166 (46) CHD CHD 160 (40) 160 (40) 23 (36) 23 (36) 215 (10) CTD CTD 9 (3) 9 (3) 10 (5) 10 (5) 639 (25) Portopulmonary Portopulmonary 2 (1) 2 (1) 3 (1) 3 (1) 136 (5) Other Other 14 (4) 14 (4) 4 (2) 4 (2) 255 (10) Group 3: Lung disease Group 3: Lung disease 42 (12) 42 (12) NE NE NE Other Other 3 (1) 3 (1) NE NE NE A/1) van Loon RL et al Circulation 2011; 2) Berger RM et al. Lancet 2012; 3) Fraisse A et al. Values given are n (%) unless otherwise indicated 1 . Berger et al. Lancet 2012. 2. Barst et al. Circulation 2012. Arch Cardiovasc Dis 2010; 4) van Loon RL et al. J Pediatr 2009; 5) Barst RJ et al. Circulation Badesch et al. Chest 2010 . 3. 2012. University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands Pediatric PAH • Comorbidities 24% - 45% NL registry • Spanish registry • TOPP registry • Multi-registry growth study • Including • Down syndrome ~10-15% • Other genetic/syndromic abnormalities ~10-30% • Non-genetic diseases ~10-20% • Multiple “associated conditions” • ~20-30% Relation to PAH - Causal? van Loon et al, 2009 - Disease modifier? Cerro et al, 2011) Ploegstra et al Berger et al. Lancet 2012 - Bystander? Lancet Respir Med 2016 Ploegstra et al Lancet Respir Med 2016 Beatrix Children ’ s Hospital Center for Congenital Heart Disease University Medical Center Groningen UMC Groningen The Netherlands 4
4/21/2018 Classification of Paediatric PH in Dutch National cohort: 1991-2005 3263 PH 160 253 0 2845 5 PH-left heart PH-lung PH- PAH disease disease/hypoxia CTEPH multifactorial 192 192 61 34% Developmental Developmental Hypoventilation lung disease lung disease 154 154 27% 2691 2691 Progressive PAH Progressive PAH Transient PAH Transient PAH 111 3 1 3 1548 1112 36 PAH- PAH- PAH- PVOD/ PPHN Flow-PAH IPAH CHD CTD HIV PCH 5 4 40 17 After 7 38 Without Pre-tricuspid Post-tricuspid shunt Accelerated APV shunt shunt shunt closure University Medical Center Groningen The Netherlands Van Loon R, et al . Circulation . 2011 WHO group 3 Data from the TOPP registries Parameter N Enrolled patients 818 WHO group 3 80 BPD 36 Interstitial lung disease 15 Congenital pulmonary hypoplasia* 14 Chronic exposure to high altitude 12 Congenital diaphragmatic hernia 10 Sleep-disorder breathing/obstructive apnea 8 COPD 2 Kyphoscoliosis* 2 Other pulmonary disease with mixed restrictive and 1 obstructive pattern** Slide courtesy of Steven Abman Multiple answers allowed University Medical Center Groningen University Medical Center Groningen 20 The Netherlands The Netherlands 5
4/21/2018 Clinical Classification PAH-CHD (shunts) PAH-CHD WSPH Nice 2014 Evolution of pulmonary vascular disease A. Eisenmenger syndrome Includes all systemic-to-pulmonary shunts resulting ? from large defects and leading to a severe increase in PVR and a reversed (pulmonary-to-systemic) or bidirectional shunt; cyanosis, erythrocytosis, and multiple organ involvement are present Grade of PVD B. PAH associated Includes moderate to large defects; PVR is mildly to with systemic-to-pulmonary shunts moderately increased, systemic-to-pulmonary shunt is still prevalent, and no cyanosis is present at rest C. PAH with small defects Small defects (usually ventricular septal defects <1 cm and atrial septal defects <2 cm of effective diameter assessed by echocardiography); clinical picture is very similar to idiopathic PAH 0 10 20 30 Years D. PAH after corrective cardiac Congenital heart disease has been corrected, but PAH surgery is still present immediately after surgery or recurs classic posttricuspid ES pretricuspid Berger, Eur Heart J 2000 several months or years after surgery in the absence of Galie, Eur Heart J 2016 significant postoperative residual lesions Beatrix Children ’ s Hospital Center for Congenital Heart Disease University Medical Center Groningen UMC Groningen The Netherlands Genotypes in Pediatric PAH PAH-CHD known PAH-genes BMPR2 ACVRL1 ENG TBX4 Total Anatomic-Physiologic Classification Levy et al. 5 4 NT 3 37 Eur Resp J 2016 14% 11% 8% 100% Harrison et al 2 1 1 NT 16 Circulation 2005 13% 7% 7% 100% Kerstjens et al 3 NT NT 3 20 J Med Genet 2013 15% 15% 100% Rosenzweig et al 8 NT NT NT 78 JHLT 2008 10% 100% Pfarr 4 2 1 (VUS) NT 29 Respir Res 2013 14% 7% 4% 100% Ramjug et al. JHLT 2016 Moceri et al IJC 2014 Alonso-Gonzalez et al IJC 2015 Compared to adult PAH, the genetic architecture of pediatric PAH seems enriched in ACVRL1 and TBX4 mutations Haworth et al, Heart 2009 (Levy et al, 2016 ) NT=Not Tested University Medical Center Groningen University Medical Center Groningen The Netherlands The Netherlands 6
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